Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]2[N:15]([CH3:53])[C:16]([CH2:18][O:19][C:20]3[CH:52]=[CH:51][C:23]([CH2:24][CH:25]4[S:29][C:28](=[O:30])[N:27](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[C:26]4=[O:50])=[CH:22][CH:21]=3)=[N:17][C:12]2=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].CO>[OH:8][C:9]1[N:14]=[C:13]2[N:15]([CH3:53])[C:16]([CH2:18][O:19][C:20]3[CH:52]=[CH:51][C:23]([CH2:24][CH:25]4[S:29][C:28](=[O:30])[NH:27][C:26]4=[O:50])=[CH:22][CH:21]=3)=[N:17][C:12]2=[CH:11][CH:10]=1
Reactant: Cn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2ccc(OCc3ccccc3)nc21
Agent: [Pd]
Solvent: CO
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(O)nc21
Yield: 15.5 %

Procedure:
A procedure similar to that described in Example 6 was repeated, except that 1.20 g of 5-{4-(5-benzyloxy-3-methylimidazo [5,4-b]pyridin-2-ylmethoxy)benzyl}-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 95), 1.80 g of 10% w/w palladium-on-charcoal and 50 ml of methanol were used, and that the product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of ethyl acetate and methanol in ratios ranging from 1:0 to 10:1 by volume as the eluent, to give 0.10 g of the title compound, melting at 240-242° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[O:6][C:5]2=O.O.[NH2:14][NH2:15]>C(O)(C)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:15][NH:14][C:5]2=[O:6]
Reactant: NN
Reactant: O=C1OC(=O)c2cc(Br)ccc21
Solvent: O
Solvent: CC(C)O
Product: O=c1[nH][nH]c(=O)c2cc(Br)ccc12
Yield: 72.3 %

Procedure:
A mixture of 5-Bromo-isobenzofuran-1,3-dione (6.0 g, 26.4 mmol) and hydrazine hydrate (1.51 mL, 32.4 mmol) in isopropanol (120 mL) was heated at reflux for 4 h. The mixture was allowed to cool and the precipitate was filtered and washed with water (50 mL). The filter cake was dried to afford the title compound (4.6 g, 72.3%) as a white solid. m/z (M+1)=241.05
Reaction SMILES: [CH:1]1([CH2:5][O:6][CH:7]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:8](=O)[CH3:9])[CH2:4][CH2:3][CH2:2]1.[BH3-]C#[N:21].[Na+]>C(Cl)Cl>[NH2:21][CH:8]([CH:7]([O:6][CH2:5][CH:1]1[CH2:4][CH2:3][CH2:2]1)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[CH3:9]
Reactant: [BH3-]C#N
Reactant: CC(=O)C(Cc1ccc(Cl)cc1)OCC1CCC1
Agent: [Na+]
Solvent: ClCCl
Product: CC(N)C(Cc1ccc(Cl)cc1)OCC1CCC1
Reaction time: 8 h

Procedure:
A solution of 3-cyclobutylmethoxy-4-(4-chlorophenyl)butan-2-one (247 mg, 0.925 mmol, obtained from Step C) in 0.5 mL CH2Cl2 was added to a stirred suspension of NH4OAc (715 mg, 9.25 mmol) and NaBH3CN (35 mg, 0.555 mmol) at room temperature and allowed to stir overnight. The reaction was quenched by the addition of 2.2 mL conc. HCl allowed to stir for 30 minutes. The solvents were evaporated under reduced pressure and the residue was partitioned between ether and water. The aqueous layer was washed two more times with ether. The combined organics were dried over Na2SO4. The crude product mixture obtained after filtration and removal of volatiles was purified by flash chromatography, eluting using mixtures of mixtures of CH2Cl2 and MeOH (100% CH2Cl2, to 5% MeOH in CH2Cl2) to provide the title compound as a yellow oil, homogeneous by TLC Rf=0.12 (5% MeOH in CH2Cl2). 500 MHz 1H NMR (CDCl3): δ 1.16 (t, 3H); 1.67 (m, 2H); 1.85 (m, 3H); 2.01 (m, 2H); 2.48 (m, 1H); 2.74 (m, 2H); 2.90 (dd, 1H); 3.15 (d quint, 2H); 3.37 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].[I-].[Na+].Cl[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28]>CN(C)C=O.CO>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: OCCCCCCCl
Agent: C[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: OCCCCCCOc1ccc(OCc2ccccc2)cc1
Reaction time: 0.08 h

Procedure:
A mixture of 106.0 g (0.53 mole) of p-benzyloxyphenol (Eastman), 28.6 g (0.53 mole) sodium methoxide (MCB) and about 2 g of sodium iodide in 600 ml of dimethylformamide is stirred for 5 minutes, after which 73 g (0.53 mole) of 6-chlorohexan-1-ol (MCB) is added, and the mixture is refluxed with stirring. The methanol formed in the reaction is allowed to distill off. After 2 hours reflux, the mixture is diluted with ice and water, 500 ml of 10% potassium hydroxide is added, and the resultant precipitate collected and dried. The solid is combined with 1 liter of butanone, refluxed and filtered. The residue is cooled, whereupon the desired product crystallizes out. The solid product is stirred with 1 liter of acetone at room temperature, the mixture is filtered to separate additional insoluble byproduct, the acetone boiled off and replaced with methanol, and the methanolic solution cooled to crystallize out the desired product, m.p. 94°-97° C.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:3]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:13][O:14][C:15]1[CH:20]=[C:19]([C:2]2[CH:6]=[CH:5][N:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)[CH:3]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: Brc1ccn(-c2ccccn2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COc1cccc(-c2ccn(-c3ccccn3)c2)c1
Temperature: 84 °C

Procedure:
2-(3-Bromo-1H-pyrrol-1-yl)pyridine (1.34 g, 2 mmol), 3-methoxyphenylboronic acid (0.61 g, 4 mmol), Pd(PPh3)4 (116 mg, 0.1 mmol) and potassium carbonate (560 mg, 4 mmol) were dissolved in a mixture of DME (18 mL) and H2O (2 mL) and degassed for 15 min with Ar (g). The reaction mixture was then heated at 84° C. for 18 h. At this time, a further 0.25 eq. of 3-methoxyphenylboronic acid (0.15 g, 1 mmol) was added and heating was continued. After a total of 42 h, the reaction mixture was cooled to rt, H2O (40 mL) and EtOAc (40 mL) were added and the reaction mixture shaken, the EtOAc layer was separated and the aqueous layer shaken with EtOAc (2×30 mL). The combined organic layers were dried over Na2SO4 and concentrated to a yellow oil. This was purified by liquid chromatography on silica gel eluting with EtOAc:hexane (3:7) to afford a white solid that was further purified by preparative HPLC to afford 2-[3-(3-methoxyphenyl)-1H-pyrrol-1-yl]pyridine as a white solid. 1H NMR (CD3Cl, 300 MHz) δ 8.52-8.54 (1H, m), 7.55 (1H, ddd), 7.38-7.39 (1H, m), 7.15-7.21 (2H, m), 6.76-6.85 (4H, m), 6.46-6.48 (1H, m), 6.41 (1H, dd). MS (ESI) 251 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.[C:9]([C:11]1[C:16]2[N:17]=[C:18]([C:20]([NH:22][CH3:23])=[O:21])[O:19][C:15]=2[C:14](F)=[C:13]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:12]=1[CH3:31])#[N:10].C(N(CC)CC)C>CS(C)=O>[C:9]([C:11]1[C:16]2[N:17]=[C:18]([C:20]([NH:22][CH3:23])=[O:21])[O:19][C:15]=2[C:14]([N:5]2[CH2:6][CH2:7][C@H:3]([N:2]([CH3:8])[CH3:1])[CH2:4]2)=[C:13]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:12]=1[CH3:31])#[N:10]
Reactant: CN(C)[C@H]1CCNC1
Reactant: CNC(=O)c1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1nc2c(C#N)c(C)c(-c3ccccc3)c(N3CC[C@H](N(C)C)C3)c2o1
Reaction time: 0.83 h

Procedure:
A dimethyl sulfoxide (1.5 ml) solution of (3S)-3-(dimethylamino)pyrrolidine (57 μl, 446 μmol) was added to a dimethyl sulfoxide (6 ml) solution of 4-cyano-7-fluoro-N,5-dimethyl-6-phenyl-1,3-benzoxazole-2-carboxamide (I-113) (115 mg, 372 μmol) and triethylamine (67 μl, 484 μmol) at 150° C., followed by stirring at the same temperature for 50 minutes under nitrogen atmosphere.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](Br)[CH:5]=[CH:4][C:3]=1[OH:9].[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[CH2:12].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>ClCCl.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:15]([O:14][C:10](=[O:13])[CH:11]=[CH:12][C:6]1[CH:5]=[CH:4][C:3]([OH:9])=[C:2]([F:1])[CH:7]=1)[CH3:16]
Reactant: Oc1ccc(Br)cc1F
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C=Cc1ccc(O)c(F)c1
Temperature: 25 °C

Procedure:
A solution of 2-fluoro-4-bromophenol 14-1 (50 g, 261.8 mmol), ethyl acrylate (34 mL), Pd(OAc)2 (2.5 g), tri-o-tolylphosphine (5 g) and triethylamine (83 mL) was heated to 100° C. in a sealed tube for 12 h. The reaction was cooled to room temperature and diluted with dichloromethane (100 mL). The organic solution was washed with 10% aq. citric acid (40 mL), satd aq NaHCO3, and brine (40 mL). The organic solution was dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (50:50 hexanes/EtOAc to 100% EtOAc) to give acrylic acid 14-2 as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][C:26]=2[C:33]([O:35]C)=[O:34])[N:8]([CH3:24])[C:9](=[O:23])[N:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C:11]=1[CH3:12])=[O:5])[CH3:2].[OH-].[Li+].O.Cl>O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][C:26]=2[C:33]([OH:35])=[O:34])[N:8]([CH3:24])[C:9](=[O:23])[N:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:22])[F:21])[CH:14]=2)[C:11]=1[CH3:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(C)C1c1ccc(C#N)cc1C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(C)C1c1ccc(C#N)cc1C(=O)O

Procedure:
4-(4-Cyano-2-methoxycarbonyl-phenyl)-3,6-dimethyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid ethyl ester (intermediate 9)(3.39 g, 6.76 mmol) and lithium hydroxide (194.4 mg, 8.11 mmol) are stirred in 1,4-dioxane (84 ml) and water (6.0 mL) at room temperature for 100 h. Water is added and the mixture is acidified with hydrochloric acid (4.0 mol/L) to a pH value of 3. The aqueous phase is extracted with dichloromethane three times. The combined organic phase is dried over MgSO4, concentrated and purified by reversed phase HPLC. Yield: 1.34 g. ESI mass spectrum: [M+H]+=488; Retention time HPLC: 1.08 min (HPLC method Z018_S04).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=2)=[C:12]([CH3:21])[C:11]([C:22](O)=[O:23])=[N:10]1.[NH2:25][N:26]1[CH2:31][CH2:30][S:29](=[O:33])(=[O:32])[CH2:28][CH2:27]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>O.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=2)=[C:12]([CH3:21])[C:11]([C:22]([NH:25][N:26]2[CH2:31][CH2:30][S:29](=[O:33])(=[O:32])[CH2:28][CH2:27]2)=[O:23])=[N:10]1
Reactant: NN1CCS(=O)(=O)CC1
Reactant: Cc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(I)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(C(=O)NN2CCS(=O)(=O)CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(I)cc1
Reaction time: 1 h
Yield: 31.4 %

Procedure:
The acid (7.5 g, 15.8 mmol) obtained from step D was taken in a 500 ml 1 neck flask equipped with a nitrogen inlet and to it 200 ml of DCM, 4-aminothiomorpholine-1,1-dioxide (2.61 g, 17.4 mmol), TBTU (5.59 g, 17.4 mmol) and DIPEA (2.25 g, 17.4 mmol) were added and the contents were stirred for 1 hour. To the reaction mixture, 100 ml of water was added and the contents were acidified to pH ˜2 using concentrated HCl. The organic layer was separated, washed with brine, dried over sodium sulphate and concentrated to give the amide (3 g, 31.2%).
Reaction SMILES: C[O:2][C:3](=[O:21])/[C:4](/[C:8]1[N:9]=[C:10]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[S:11][CH:12]=1)=[CH:5]\[CH2:6][CH3:7].[OH-].[Na+].Cl>C(O)(C)C.O>[C:17]([O:16][C:14]([NH:13][C:10]1[S:11][CH:12]=[C:8](/[C:4](=[CH:5]/[CH2:6][CH3:7])/[C:3]([OH:21])=[O:2])[N:9]=1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC/C=C(\C(=O)OC)c1csc(NC(=O)OC(C)(C)C)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CC/C=C(\C(=O)O)c1csc(NC(=O)OC(C)(C)C)n1
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 77.8 %

Procedure:
To a solution of (Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-pentenoic acid methyl ester (425 mg: 1.4 mMol.) in isopropanol (1.3 ml) and water (3.7 ml) is added sodium hydroxide (163 mg: 4.1 mMol.), and the mixture is stirred at 65° C. for 90 minutes. The reaction mixture is adjusted to pH 4.7 with 35% hydrochloric acid and kept at 20° C. for 1 hour. The separating crystals are collected by filtration, washed with isopropanol, and dried to give (Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-pentenoic acid (325 mg). Yield: 86%. mp. 187° C. (decomposition). NMR δ(CDCl3) ppm: 1.09(t, J=7.6 Hz, 3H), 1.55(s, 9H) 2.64(qd, J=7.6 Hz, 2H), 6.69(t, J=7.6 Hz, 1H), 6.96(s, 1H). IR ν(CHCl3) cm-1 : 3160, 2548br, 1721, 1685, 1556, 1252, 1156.
Reaction SMILES: O1CCCC1.[Cl-].[Al+3].[Cl-].[Cl-].[C:10]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]2[C:22](=[O:23])[CH2:21][C:20]3[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=3[S:18][C:17]=2[CH:28]=1)#[N:11].[N-:29]=[N+:30]=[N-:31].[Na+]>O>[NH:29]1[C:10]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]3[C:22](=[O:23])[CH2:21][C:20]4[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=4[S:18][C:17]=3[CH:28]=2)=[N:11][N:31]=[N:30]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCc1ccc2c(c1)Sc1ccccc1CC2=O
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1Cc2ccccc2Sc2cc(Cc3nnn[nH]3)ccc21

Procedure:
Add to 25 cc. of tetrahydrofuran cooled in an ice bath 1.59 gm. (11.9 mmole) of aluminum chloride, 1.33 gm. (5.25 mmole) of 3-cyanomethyl-10,11-dihydro-11-oxodibenzo[b,f]thiepin and 1.55 gm. (23.8 mmole) of sodium azide. Reflux the mixture for 19 hours, cool, dilute with water and acidify. Extract the mixture into ethyl acetate and evaporate. Triturate the residue in ether and separate the title product by filtration.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[Br-].[Mg+2].[CH2:10]=[CH2:11].[Br-]>O1CCCC1.CO>[C:10]([C:4]1([OH:7])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)#[CH:11]
Reactant: O=C1CCOCC1
Reactant: C=C
Agent: [Br-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: CO
Product: C#CC1(O)CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.2 %

Procedure:
A solution of tetrahydro-4H-pyran-4-one (1.25 g, 12.5 mmol) in tetrahydrofuran (10 mL) was cooled to 0° C. and then treated with a 0.5M solution of ethylene magnesium bromide in tetrahydrofuran (40 mL, 20 mmol). The mixture was stirred at 0° C. for 2 h and at 25° C. for 4 h. The resulting mixture was cooled to 0° C. and then diluted with methanol (10 ml). The solvents were concentrated in vacuo, and the residue was extracted with a saturated aqueous ammonium chloride solution and ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dried in vacuo to afford solid 4-ethynyl-tetrahydro-pyran-4-ol (1.2 g, 95.2%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[CH:3]=1.[CH2:23]([O:25][C:26](=[O:34])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=1)[CH3:24].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH2:23]([O:25][C:26](=[O:34])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([O:33][C:2]2[CH:3]=[C:4]([NH:10][CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=3)[N:5]=[C:6]([S:8][CH3:9])[N:7]=2)[CH:28]=1)[CH3:24]
Reactant: CCOC(=O)c1cccc(O)c1
Reactant: COc1ccc(CCNc2cc(Cl)nc(SC)n2)cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cccc(Oc2cc(NCCc3ccc(OC)c(OC)c3)nc(SC)n2)c1
Temperature: 90 °C
Yield: 83.5 %

Procedure:
A mixture of (6-dhloro-2-methylsulfanyl-pyrimidin-4-yl)-[2-(3,4-dimethoxy-phenyl)-ethyl]-amine [250 mg, 0.74 mmol, Intermediate (31)], 3-hydroxy-benzoic acid ethyl ester (0.18 g, 1.1 mmol), and Cs2CO3 (0.48 g, 1.48 mmol) in DMF (4 mL) is heated to 90° C. for 15 h. The mixture is diluted with water, and extracted with EtOAc. The extracts are washed (water), dried (MgSO4), filtered, concentrated, and chromatographed (silica gel, 30% EtOAc in Heptane) to afford 3-{6-[2-(3,4-dimethoxy-phenyl)-ethylamino]-2-methylsulfanyl-pyrimidin-4-yloxy}-benzoic acid ethyl ester [0.29 g 83%, Intermediate (71)]. LCMS: RT=3.7 minutes, MS: 470 (M+H).
Reaction SMILES: C(O[C:4]([C:6]1([CH2:13][CH2:14]OC)[CH2:11][CH2:10][NH:9][C:8](=[O:12])[CH2:7]1)=[O:5])C.[F:17][C:18]([F:28])([F:27])[CH2:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1>[Cl-].C[Al+]C>[F:17][C:18]([F:27])([F:28])[CH2:19][C:20]1[CH:26]=[CH:25][C:23]([N:24]2[CH2:14][CH2:13][C:6]3([CH2:11][CH2:10][NH:9][C:8](=[O:12])[CH2:7]3)[C:4]2=[O:5])=[CH:22][CH:21]=1
Reactant: CCOC(=O)C1(CCOC)CCNC(=O)C1
Reactant: Nc1ccc(CC(F)(F)F)cc1
Agent: C[Al+]C
Agent: [Cl-]
Product: O=C1CC2(CCN1)CCN(c1ccc(CC(F)(F)F)cc1)C2=O

Procedure:
This material was prepared as a white solid (0.72 g) in analogy to example 1 step D) from 4-(2-methoxy-ethyl)-2-oxo-piperidine-4-carboxylic acid ethyl ester (1.03 g), dimethylaluminium chloride (0.9 M in hexane, 20 ml) and 4-(2,2,2-trifluorethyl)aniline (1.2 g). MS (ESI): 327.13 (MH−).
Reaction SMILES: [CH:1]1([NH:5][N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[C:8]([C:17]3[NH:22][C:21]4[CH:23]=[CH:24][C:25]([NH:27][S:28](=[O:41])(=[O:40])[NH:29][C:30]([O:32][CH2:33][C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)=[O:31])=[CH:26][C:20]=4[S:19](=[O:43])(=[O:42])[N:18]=3)[C:7]2=[O:44])[CH2:4][CH2:3][CH2:2]1.[CH3:45][Si](C=[N+]=[N-])(C)C>O1CCCC1.CO>[CH:1]1([NH:5][N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[C:8]([C:17]3[NH:22][C:21]4[CH:23]=[CH:24][C:25]([NH:27][S:28](=[O:41])(=[O:40])[N:29]([CH3:45])[C:30]([O:32][CH2:33][C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)=[O:31])=[CH:26][C:20]=4[S:19](=[O:43])(=[O:42])[N:18]=3)[C:7]2=[O:44])[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(NS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3ccccc3n(NC3CCC3)c1=O)N2)OCc1ccccc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C(=O)OCc1ccccc1)S(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3ccccc3n(NC3CCC3)c1=O)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.5 %

Procedure:
A solution of the product of Example 465 (0.045 g, 0.07 mmol) in 1:1 tetrahydrofuran/methanol (2 ml) at −10° C. was treated dropwise with trimethylsilyl diazomethane (2.0 M in hexanes, 70 μL, 0.14 mmol), stirred at 25° C. for 16 hours and concentrated under reduced pressure to provide the title compound (0.045 g, 98% yield).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH2:9][NH:10][CH:11]2[CH2:19][C:18]3[C:13](=[CH:14][C:15]([N+:20]([O-])=O)=[CH:16][CH:17]=3)[CH2:12]2)[CH:6]=[CH:7][CH:8]=1.CC(O)=[O:25].O>[Zn]>[CH3:3][CH:8]([OH:25])[CH3:7].[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([CH2:9][NH:10][CH:11]2[CH2:19][C:18]3[C:13](=[CH:14][C:15]([NH2:20])=[CH:16][CH:17]=3)[CH2:12]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)O
Reactant: O=[N+]([O-])c1ccc2c(c1)CC(NCc1cccc(Cl)c1)C2
Agent: Cl
Agent: [Zn]
Solvent: O
Product: CC(C)O
Product: Nc1ccc2c(c1)CC(NCc1cccc(Cl)c1)C2
Reaction time: 0.08 h

Procedure:
To 2-((3-chlorophenyl)methyl)amino-6-nitroindane hydrochloride (2.1 g, 6.13 mmol) in 85% AcOH/H2O (40 ml) was added zinc metal (1.6 g, 24.3 mmol). The mixture was stirred for 5 min, filtered through celite, and evaporated to an oil. The oil was dumped into basic water and extracted with chloroform (3×20 ml). The combined extracts were washed with water, dried over MgSO4, filtered and concentrated to an oil. Treatment with IPA/HCl yielded 2-((3-chlorophenyl)methyl)amino-6-aminoindane: (1.5 g, 70%); m.p.>270° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([OH:14])=O)[C:6]=2[CH:15]=1.[Cl:16][C:17]1[CH:28]=[CH:27][C:20]2[NH:21][C:22]([CH2:24][NH:25][CH3:26])=[N:23][C:19]=2[CH:18]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>O.CN(C=O)C>[Cl:16][C:17]1[CH:28]=[CH:27][C:20]2[NH:21][C:22]([CH2:24][N:25]([CH3:26])[C:12](=[O:14])[CH2:11][N:7]3[C:6]4[CH:15]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[S:9][C:8]3=[O:10])=[N:23][C:19]=2[CH:18]=1
Reactant: O=C(O)Cn1c(=O)sc2ccc(Cl)cc21
Reactant: CNCc1nc2cc(Cl)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CN(Cc1nc2cc(Cl)ccc2[nH]1)C(=O)Cn1c(=O)sc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.4 %

Procedure:
To a mixture of (5-chloro-2-oxo-1,3-benzothiazol-3(2H)-yl)acetic acid (300 mg), 1-(5-chloro-1H-benzimidazol-2-yl)-N-methylmethanamine (265 mg) and DMF (20 mL) were added TEA (687 μL), HOBt (200 mg), and WSC.HCl (283 mg), followed by stirring at room temperature overnight. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was washed with water, a saturated aqueous NaHCO3 solution, and brine in this order, dried over Na2SO4, and then concentrated under reduced pressure. The obtained solid was washed with EtOAc to obtain N-[(5-chloro-1H-benzimidazol-2-yl)methyl]-2-(5-chloro-2-oxo-1,3-benzothiazol-3(2H)-yl)-N-methylacetamide (339 mg).
Reaction SMILES: [C:1]1([Li])[CH:16]=[CH:15][CH:14]=[C:13]2[C:2]=1[CH:3]=[C:4]1[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[C:5]12.[Cl-].[Cl-].[Cl-].C1([Zr+3:26])C=CC=C1>C1(C)C=CC=CC=1.C(OCC)C>[C:1]1([Zr:26])[CH:16]=[CH:15][CH:14]=[C:13]2[C:2]=1[CH:3]=[C:4]1[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[C:5]12
Reactant: [Li]c1cccc2c1C=C1C2=Nc2ccccc21
Reactant: [Zr+3]C1C=CC=C1
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: [Zr]c1cccc2c1C=C1C2=Nc2ccccc21
Reaction time: 8 h

Procedure:
A sample of the indeno[1,2-b]indolyl lithium salt produced above (10 g, 42 mmol) is dissolved in toluene (95 mL) to produce an orange slurry. Diethyl ether (35 mL) is added slowly to give an orange solution. This solution is added over 15 min. at room temperature with stirring to a slurry of cyclopentadienylzirconium trichloride (11 g, 42 mmol) in toluene (190 mL) and diethyl ether (190 mL). The mixture turns deep red and is kept at room temperature overnight. The slurry is filtered to recover a red solid, which is washed with toluene (200 mL) and dried under vacuum. Yield of complex 10: 16.5 g. The 1H NMR spectrum is consistent with the proposed structure:
Reaction SMILES: CO[C:3]1[C:16]2[C:15]3[N:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:9](=[O:17])[N:8]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.[C:27](OCC)(=[O:29])C.ClCCl.CO>[Pd]>[CH3:27][O:29][C:5]1[CH:4]=[CH:3][C:16]2[C:15]3[NH:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9](=[O:17])[N:8]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[C:7]=2[CH:6]=1
Reactant: COc1ccc(Cn2c(=O)c3cccnc3c3c(OC)cccc32)cc1
Reactant: CCOC(C)=O
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(Cn2c(=O)c3c(c4ccc(OC)cc42)NCCC3)cc1
Reaction time: 18 h
Yield: 99 %

Procedure:
To a stirred solution of the compound of 8-methoxy-6-(4-methoxybenzyl)benzo[h][1,6]naphthyridine-5(6H)-one (192.4 mg, 0.555 mmol) prepared in step 3 in ethyl acetate/dichloromethane/methanol, was added 10%-palladium (Pd) (20 mg) and the mixture was stirred for 18 hours under hydrogen gas. Once the reaction was completed, 10%-palladium (Pd) was filtered out, and the filtrate was concentrated under reduced pressure to obtain the title compound (192.7 mg, yield: 99%, ivory solid).